[go: up one dir, main page]

WO2023104019A1 - 二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中的应用 - Google Patents

二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中的应用 Download PDF

Info

Publication number
WO2023104019A1
WO2023104019A1 PCT/CN2022/136863 CN2022136863W WO2023104019A1 WO 2023104019 A1 WO2023104019 A1 WO 2023104019A1 CN 2022136863 W CN2022136863 W CN 2022136863W WO 2023104019 A1 WO2023104019 A1 WO 2023104019A1
Authority
WO
WIPO (PCT)
Prior art keywords
self
depression
adolescent
started
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/136863
Other languages
English (en)
French (fr)
Inventor
於邱黎阳
鲍进
朱承刚
罗木鹏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Institute of Advanced Technology of CAS
Original Assignee
Shenzhen Institute of Advanced Technology of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Institute of Advanced Technology of CAS filed Critical Shenzhen Institute of Advanced Technology of CAS
Publication of WO2023104019A1 publication Critical patent/WO2023104019A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention belongs to the field of medicine, and in particular relates to the application of dihydronicotinamide ribose and nicotinamide mononucleotide in treating adolescent self-injury and depression induced by adverse environmental factors.
  • Depression is an affective mental disorder. The clinical manifestation is "three lows"-depressed mood, loss of interest, lack of motivation, and lasts for at least 2 weeks. 80% of adolescents with depression have non-suicidal self-injury behaviors.
  • Non-suicidal self-injury behaviors refer to individuals taking a series of repeated, deliberate, and direct injuries to their bodies without suicidal thoughts, and are not socialized. permitted behavior.
  • Self-injury is divided into 5 categories: cuts or burns, self-poisoning, intentional non-recreational risk taking, self-beating, and other self-injurious behaviors. Among them, bleeding from cuts is the most common. At present, non-suicidal self-injury behavior is regarded clinically as one of the symptoms caused by depression, and adolescents with depression report that they can relieve negative emotions in this way.
  • Antidepressant drugs commonly used in clinical practice include SSRIs, SNRIs, and NaSSAs. It mainly acts on neurotransmitters such as dopamine, norepinephrine and 5-hydroxytryptamine. Mood stabilizers are also used to treat treatment-resistant depression.
  • the disadvantages of antidepressants such as SSRIs, SNRIs, and NaSSAs are slow drug effects and poor therapeutic effects, and antidepressants have a series of side effects. These side effects involve the functions of various systems throughout the body, including sleep disturbances, appetite changes, headaches, nausea, digestive disorders, liver toxicity, and decreased sexual function.
  • mood stabilizers are usually accompanied by significant adverse reactions.
  • Some mood stabilizers, such as lithium salts, divalproex sodium, etc. have a relatively strict blood concentration window, and serious effects will occur after exceeding the ideal blood concentration window, so the use of such drugs in clinical practice usually requires Accompanied by blood concentration monitoring to ensure drug efficacy and control side effects.
  • NAD+ coenzyme nicotinamide adenine dinucleotide
  • NAD+ precursors such as nicotinamide riboside (NR ) and nicotinamide mononucleotide (NMN) can improve symptoms of muscle atrophy1 and neurodegenerative diseases2 in mouse models.
  • NR nicotinamide riboside
  • NN nicotinamide mononucleotide
  • NAD+ supplementation programs based on NAD+ precursors have positive effects on the nervous system, including significantly improving cognitive performance, repairing neurodegeneration caused by trauma, and improving neurodegenerative diseases.
  • NMN and NRH can improve the symptoms of adolescent depression caused by behavioral modeling and self-injury caused by drug modeling.
  • Vazquez-Rosa E.; Shin, MK; Dhar, M.; Chaubey, K.; Cintron-Perez, CJ; Tang, X.; , S.; Franke, K.; Crosby, DR; Schroeder, R.; Emery, J.; Yin, TC; Fujioka, H.; Reynolds, JD; Harper, MM; Jain, MK; A20 treatment one year after TBI in mice repairs the blood-brain barrier, arrests chronic neurodegeneration, and restores cognition. Proc Natl Acad Sci USA 2020, 117 (44), 27667-27675.
  • the antidepressant active ingredient provided by the present invention is ⁇ -nicotinamide mononucleotide (NMN) or ⁇ -dihydronicotinamide riboside (NRH), which is used in the treatment or prevention of self-injury in adolescence and depression induced by adverse environmental factors in developmental stages.
  • NNN ⁇ -nicotinamide mononucleotide
  • NH ⁇ -dihydronicotinamide riboside
  • ⁇ -nicotinamide mononucleotide can reduce the anxiety associated with self-injury thoughts and/or feelings of subjects in the preparation, or reduce the self-injury thoughts and/or feelings of subjects due to anxiety. Uses in Drugs of Feeling.
  • the subject is an adolescent subject.
  • the adolescent subjects are humans aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development.
  • the subject has self-harm thoughts and/or feelings due to drug-induced anxiety.
  • Another aspect of the invention provides a method for reducing self-harming thoughts and/or feelings comprising administering ⁇ -nicotinamide mononucleotide to a subject in need thereof.
  • the subject is an adolescent subject.
  • the adolescent subjects are humans aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development.
  • the subject has self-harm thoughts and/or feelings due to drug-induced anxiety.
  • Another aspect of the present invention provides a drug for reducing thoughts and/or feelings of self-harm, wherein the drug uses ⁇ -nicotinamide mononucleotide as an active ingredient.
  • the medicine is an oral medicine or an injection medicine.
  • Another aspect of the present invention provides a use of ⁇ -dihydronicotinamide riboside in the preparation of a drug for treating or preventing adolescent depression.
  • the pubertal depression patients are human beings aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development.
  • adolescent depression is induced by the stress of long-term stressful events.
  • adolescent depression is induced by stressful events in early life.
  • Another aspect of the present invention provides the use of ⁇ -dihydronicotinamide riboside in the preparation of drugs for the desire to survive in normal subjects;
  • Another aspect of the present invention provides a method for preventing or treating adolescent depression with ⁇ -dihydronicotinamide riboside, the method comprising administering ⁇ -dihydronicotinamide riboside to a subject in need.
  • Another aspect of the present invention provides a drug for preventing or treating adolescent depression, which uses ⁇ -dihydronicotinamide riboside as an active ingredient.
  • the medicine is an oral medicine or an injection medicine.
  • the present invention provides the first discovery that NMN or NRH as a single active ingredient has an inhibitory effect on adolescent depression and self-injury behavior.
  • the antidepressant active ingredients provided by the invention can significantly reduce the self-injury bleeding behavior and anxiety behavior related to adolescent depression, and its effectiveness reaches the level similar to mood stabilizers.
  • the active ingredient NMN provided by the invention has no toxic and side effects as confirmed in various animal experiments and clinical experiments.
  • Figure 1 shows the performance statistics of tail suspension time and forced swimming test: NRH administration group significantly improved the tail suspension time of depression model mice.
  • NMN Using chemically pure NMN as raw material, it is further purified by preparative HPLC, using methanol/water as the mobile phase, collecting the purified peaks, and freeze-drying the collected liquid to obtain purified NMN for experiments.
  • NRH Under Ar atmosphere, nicotinamide riboside ( NR ) (2.90 g, 10.0 mmol, 1.0 eq.), K 2 HPO 4 (3.48 g, 20.0 mmol, 2.0 eq.) and 50 mL deionized water, and at 0 o Stirred under the condition of C for 5 minutes, then slowly added Na to the mixture in batches. 2 S 2 o 6 (1.74 g, 10.0 mmol, 1.0 eq.), continue to react at this temperature for 1 hour after the addition is complete.
  • Embodiment 2 adolescent depression model
  • the adolescent depression model was prepared by mother-infant separation, which is one of the commonly used models for constructing stressful events in early life.
  • mother-infant separation results in changes in corticosterone secretion, but the dynamics of corticosterone induced by mother-infant separation are significantly different from those in a mouse model of depression after repeated injections of corticosterone (Iijima, M. ; Ito, A.; Kurosu, S.; Chaki, S., Pharmacological characterization of repeated corticosterone injection-induced depression model in rats. Brain Res 2010, 1359 , 75-80.).
  • mice were given normal saline and NRH-containing solutions respectively. Then two classic experiments of tail suspension and forced swimming were carried out.
  • the experimental results showed that the young rats given NRH showed a stronger desire to survive during puberty, and the struggling time when the tail was suspended was longer than that of the control group (Fig. 1 left).
  • the depression model (D) mice showed lower helpless abandonment behavior than the control mice (Control), however, the active survival behavior of the mice given NRH, regardless of the depression model, was higher than that of the control mice.
  • the depression modeling group was strong (Fig. 1 right).
  • mice After the depression model was implemented in the young mice, the young mice showed a higher depression phenotype than the control group at puberty. In the same experiment, the mice given the same level of modeling and intraperitoneal NRH injection showed relief of the depression phenotype.
  • Embodiment 3 reduces the self-injury behavior experiment that anxiety brings
  • Drug-induced anxiety was administered to adolescent mice, and it was observed that more than 75% of the mice entered a state of high anxiety within 10 minutes after drug injection, and then exhibited self-biting to bleeding behavior (SIB) within 100 minutes, and self-injury was Extremely depressive/anxiety phenotype. Mice given NMN intraperitoneally half an hour before drug-induced anxiety had a greatly reduced rate of self-injury phenotype, similar to lithium, a known anxiety-relieving drug.
  • self-injury is usually defined as intentional injury to body tissue, and there is a certain proportion among adolescents, and there is a trend of increasing incidence year by year, which includes self-injury and self-poisoning.
  • the most common form of self-injury is skin cutting, but self-injury also covers a wide range of behaviors, including but not limited to burning, scratching, punching or knocking on body parts, interfering with wound healing (eg, compulsive skin scratching syndrome), hair pulling (such as trichotillomania), and ingestion of toxic substances or objects.
  • Suicide is not usually the purpose or goal of self-injury, but self-injury can be potentially life-threatening.
  • self-injury can occur at any age, it is especially common in adolescents and young adults, usually between the ages of 12 and 24.
  • Motives for self-injury in adolescents vary and are often related to a history of childhood trauma.
  • NMN can inhibit self-injury behavior caused by anxiety in adolescent subjects through experiments on mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

β-烟酰胺单核苷酸在制备降低受试者伴有自伤想法和/或感受的焦虑、或者在制备降低受试者由于焦虑带来的自伤想法和/或感受的药物中的用途。β-二氢烟酰胺核糖在制备治疗或预防青春期抑郁的药物中的用途。β-烟酰胺单核苷酸或β-二氢烟酰胺核糖作为单一有效成分对于青春期抑郁以及自伤行为具有抑制效果。

Description

二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中的应用 技术领域
本发明属于医药领域，具体涉及二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中应用。
 背景技术
抑郁症属于情感性精神障碍疾病。临床体现为“三低”——情绪低落，兴趣减退，动力不足，且持续至少2周以上。患有抑郁症的青少年中有80%出现非自杀性自伤行为，非自杀性自伤行为是指个体在无自杀意念的情况下采取一系列反复、故意、直接伤害自己身体，且不被社会所允许的行为。自伤分为5类：割伤或烧伤，自我毒害，故意的非娱乐性冒险，自我殴打，以及其他自伤行为。其中割伤出血行为最为常见。目前临床将非自杀性自伤行为视为抑郁症导致的症状之一，青少年抑郁症患者自述通过这种方式能排解负面的情绪。
目前临床常用的抗抑郁药物包括SSRI类、SNRI类、NaSSA类等。主要作用于多巴胺、去甲肾上腺素和5-羟色胺等神经递质。心境稳定剂也被用来治疗难治性抑郁症。SSRI类、SNRI类、NaSSA类等抗抑郁药的缺点是药效慢和治疗效果不佳，抗抑郁药物有一系列的副作用。这些副作用涉及全身各系统功能，包括睡眠紊乱、食欲改变、头痛、恶心、消化紊乱、肝脏毒性、性功能下降等。
常用心境稳定剂通常伴随明显的不良反应。部分心境稳定剂，如锂盐、双丙戊酸钠等，有较为严格的血药浓度窗口，超过理想血药浓度窗口后会出现严重幅度作用，因此在临床实践中该类药物的使用通常需要伴随血药浓度监测以确保达到药效并控制毒副作用。
辅酶烟酰胺腺嘌呤二核苷酸（NAD+）参与了细胞的DNA修复、线粒体呼吸和炎症响应等重要生命过程。在神经科学领域，通过NAD+前体和NAD+代谢调控药物提高细胞内的NAD+浓度可以显著提高认知能力、修复由创伤造成的神经退行和改善神经退行性疾病。补充烟酰胺核糖（NR）、烟酰胺单核苷酸（NMN）等NAD+前体可以在小鼠模型中改善肌肉萎缩 1、神经退行性疾病等症状 2。利用药物分子（如P7C3类分子）可以激活NAD+生物合成限速酶NAMPT，起到显著神经保护效果 3。其衍生物P7C3-A20在创伤性脑损伤小鼠模型中可以修复脑损伤引起的血脑屏障破损，遏止慢性神经退行，恢复小鼠认知 4。但是尚无背景技术报道NAD+前体NMN和二氢烟酰胺核糖（dihydronicotinamide riboside, NRH）在改善抑郁症和抑郁相关的自伤现象中的应用。
以NAD+前体为基础的NAD+补充方案对神经系统有积极作用，包括显著提高认知能力、修复由创伤造成的神经退行和改善神经退行性疾病等。但是NMN和NRH改善由行为造模引发的青春期抑郁症状和药物造模引发的自伤现象尚无报道。
1.      Zhang, H.;  Ryu, D.;  Wu, Y.;  Gariani, K.;  Wang, X.;  Luan, P.;  D'Amico, D.;  Ropelle, E. R.;  Lutolf, M. P.;  Aebersold, R.;  Schoonjans, K.;  Menzies, K. J.; Auwerx, J., NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 2016, 352 (6292), 1436-43.
2.      McElroy, G. S.;  Reczek, C. R.;  Reyfman, P. A.;  Mithal, D. S.;  Horbinski, C. M.; Chandel, N. S., NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction. Cell Metab 2020, 32 (2), 301-308 e6.
3.    Wang, G.;  Han, T.;  Nijhawan, D.;  Theodoropoulos, P.;  Naidoo, J.;  Yadavalli, S.;  Mirzaei, H.;  Pieper, A. A.;  Ready, J. M.; McKnight, S. L., P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 2014, 158 (6), 1324-1334.
4.      Vazquez-Rosa, E.;  Shin, M. K.;  Dhar, M.;  Chaubey, K.;  Cintron-Perez, C. J.;  Tang, X.;  Liao, X.;  Miller, E.;  Koh, Y.;  Barker, S.;  Franke, K.;  Crosby, D. R.;  Schroeder, R.;  Emery, J.;  Yin, T. C.;  Fujioka, H.;  Reynolds, J. D.;  Harper, M. M.;  Jain, M. K.; Pieper, A. A., P7C3-A20 treatment one year after TBI in mice repairs the blood-brain barrier, arrests chronic neurodegeneration, and restores cognition. Proc Natl Acad Sci U S A 2020, 117 (44), 27667-27675。
技术问题
本发明提供的抗抑郁有效成分为β-烟酰胺单核苷酸（NMN）或β-二氢烟酰胺核糖（NRH），在治疗或预防青春期自伤和发育阶段恶劣环境因素诱导抑郁中应用。
 技术解决方案
本发明一个方面提供了β-烟酰胺单核苷酸在制备降低受试者伴有自伤想法和/或感受的焦虑、或者在制备降低受试者由于焦虑带来的自伤想法和/或感受的药物中的用途。
进一步地，所述的受试者为青少年受试者。
进一步地，所述的青少年受试者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠。
进一步地，所述的受试者产生自伤想法和/或感受的原因为药物诱导的焦虑。
本发明另一个方面提供了一种用于降低自伤想法和/或感受的方法，所述方法包括向有需要的受试者给予β-烟酰胺单核苷酸。
进一步地，所述的受试者为青少年受试者。
进一步地，所述的青少年受试者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠。
进一步地，所述的受试者产生自伤想法和/或感受的原因为药物诱导的焦虑。
本发明再一个方面提供了用于降低自伤想法和/或感受的药物，所述药物中以β-烟酰胺单核苷酸为有效成分。
进一步地，所述药物为口服药物、注射药物。
本发明再一个方面提供了一种β-二氢烟酰胺核糖在制备治疗或预防青春期抑郁的药物中的用途。
进一步地，所述的青春期抑郁的患者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠。
进一步地，所述的青春期抑郁由于长期压力事件应激诱导。
进一步地，所述的青春期抑郁是由于生命早期压力事件应激诱导产生的。
本发明再一个方面提供了β-二氢烟酰胺核糖在制备正常受试者求生欲望的药物中的用途；
本发明再一个方面提供了β-二氢烟酰胺核糖在预防或治疗青春期抑郁的方法，所述方法包括向有需要的受试者给予β-二氢烟酰胺核糖。
本发明再一个方面提供了预防或治疗青春期抑郁的药物，所述药物中以β-二氢烟酰胺核糖为有效成分。
进一步地，所述药物为口服药物、注射药物。
 有益效果
本发明提供首次发现了NMN或NRH作为单一有效成分对于青春期抑郁以及自伤行为具有抑制效果。
本发明提供的抗抑郁有效成分显著降低了和青春期抑郁相关的自伤出血行为和焦虑行为，其有效程度达到了类似心境稳定剂的水平。本发明提供的有效成分NMN在多种动物实验和临床实验证实没有毒副作用。
 附图说明
图1为悬尾时间和强迫游泳实验表现统计：NRH给药组显著提高了抑郁造模小鼠的悬尾时间。
图2. 小鼠在青春期焦虑模型中出现自伤（SIB）情况统计：出现自伤得分为1，没有自伤情况得分为0。NMN给药明显降低了SIB的发生概率。
 本发明的实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
实施例1NMN与NRH的纯化和制备
NMN：以化学纯NMN为原料，通过制备型HPLC对其进一步纯化，以甲醇/水为流动相，收集纯化峰，对收集液进行冷冻干燥，即获得实验用纯化NMN。
Figure dest_path_image001
NRH ：在Ar氛围下，向一干燥Schlenk反应瓶中依次加入烟酰胺核糖（ NR） (2.90 g, 10.0 mmol, 1.0 eq.)、K 2HPO 4 (3.48 g, 20.0 mmol, 2.0 eq.)和50 mL去离子水，并在0 oC条件下搅拌5分钟，再分批向该混合液中缓慢加入Na 2S 2O 6 (1.74 g, 10.0 mmol, 1.0 eq.)，加完后继续于此温度反应1小时。HPLC监测反应，待原料基本转化完后，反应液用C18反向制备柱进行分离纯化（H 2O : MeOH = 95:5），收集液进行冷冻干燥，可得纯净的目标产物 NRH，黄色固体 (1.45g, 57% yield)。
Figure dest_path_image002
实施例2青春期抑郁模型
通过母婴分离方法制备青春期抑郁模型,母婴分离是构建生命早期压力事件的常用模型之一。在小鼠中，母婴分离现象会导致皮质酮分泌的变化，但母婴分离导致的皮质酮动态变化与重复注射皮质酮以构建抑郁小鼠模型时的动态特点有显著差异(Iijima, M.;  Ito, A.;  Kurosu, S.; Chaki, S., Pharmacological characterization of repeated corticosterone injection-induced depression model in rats. Brain Res 2010, 1359, 75-80.)。研究表明，以母婴分离为代表的生命早期压力事件除诱发焦虑外，还可导致脑肠轴功能异常，诱发肠易激综合征(O'Mahony, S. M.;  Hyland, N. P.;  Dinan, T. G.; Cryan, J. F., Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berl) 2011, 214 (1), 71-88.)；同时还可诱导下丘脑室旁核神经功能异常，影响去甲肾上腺素水平和学习能力(Shionoya, K.;  Moriceau, S.;  Bradstock, P.; Sullivan, R. M., Maternal attenuation of hypothalamic paraventricular nucleus norepinephrine switches avoidance learning to preference learning in preweanling rat pups. Horm Behav 2007, 52 (3), 391-400.)，与重复注射皮质酮构建的抑郁模型代表了不同的病理特点。采用未开始性发育的P18-P20年龄组开始性发育的青春期P30-P45年龄组进行母婴分离造模，对幼鼠实施抑郁造模后，分别给与小鼠生理盐水以及含有NRH的溶液。然后进行悬尾和强迫游泳两个经典实验。
实验结果显示给予NRH的幼鼠在青春期表现出更强的求生欲望，表现为悬尾时挣扎时间比对照组更久（图1左）。在强迫游泳实验中，抑郁造模（D）小鼠比对照小鼠（Control）表现出更低的无助放弃行为，然而给予NRH的小鼠，无论是否抑郁造模，其主动求生行为比单纯抑郁造模组强烈（图1右）。
对幼鼠实施抑郁造模后，幼鼠在青春期表现出比对照组更高的抑郁表型，同期试验中给予同等水平造模并同时给予腹腔NRH注射的小鼠出现抑郁表型缓解现象。
实施例3降低焦虑带来的自伤行为实验
对青春期小鼠实施药物诱导焦虑，可以观察到75%以上的小鼠在药物注射后10分钟内进入高度焦虑状态，而后在100分钟内出现啃咬自己至出血的行为(SIB)，自伤为极端抑郁/焦虑表型。在药物诱导焦虑前半小时腹腔给予NMN的小鼠出现自伤表型的比率大大降低，与已知的缓解焦虑药物锂盐类似。
在发明中，自伤通常被定义为故意伤害身体组织，而在青少年中存在一定比例，并有逐年高发的态势，其包括自我伤害和自我毒害。自伤最常见的形式是皮肤切割，但自伤同样涵盖了广泛范围的行为，包括但不限于灼烧、划伤、猛击或敲打身体部位、干扰伤口愈合(例如，强迫性皮肤搔抓症症)、拔毛(例如拔毛症)以及摄入有毒物质或物体。通常而言，自杀不是自伤行为的目的或目标，但是自伤可能会潜在地危及生命。尽管自伤在任何年龄都可发生，但在青少年中和青年时期尤其常见，通常在12岁至24岁之间出现。青少年自伤的动机不同，其往往与幼年创伤史有关。
上述实施例通过小鼠实验证明了NMN具有抑制青春期受试者由于焦虑导致的自伤行为。

Claims (10)

  1. β-烟酰胺单核苷酸在制备降低受试者伴有自伤想法和/或感受的焦虑、或者在制备降低受试者由于焦虑带来的自伤想法和/或感受的药物中的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述的受试者为青少年受试者。
  3. 根据权利要求2所述的用途，其特征在于，所述的青少年受试者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠。
  4. 根据权利要求3所述的用途，其特征在于，所述的受试者产生自伤想法和/或感受的原因为药物诱导的焦虑。
  5. 一种用于降低伴有自伤想法和/或感受的焦虑或者降低由于焦虑带来的自伤想法和/或感受的方法，其特征在于，所述方法包括向有需要的受试者给予β-烟酰胺单核苷酸；
    优选地，所述的受试者为青少年受试者；
    更优选地，所述的青少年受试者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠；
    更优选地，所述的受试者产生伴有自伤想法和/或感受的原因为药物诱导的焦虑。
  6. 一种用于降低伴有自伤想法和/或感受的焦虑的药物，其特征在于，所述药物中以β-烟酰胺单核苷酸为有效成分；
    优选地，所述药物为口服药物、注射药物。
  7. β-二氢烟酰胺核糖在制备治疗或预防青春期抑郁的药物中的用途；
    优选地，所述的青春期抑郁的患者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠；
    更优选地，所述的青春期抑郁由于长期压力事件应激诱导；
    更优选地，所述的青春期抑郁是由于生命早期压力事件应激诱导产生的。
  8. β-二氢烟酰胺核糖在制备正常受试者求生欲望的药物中的用途；
    优选地，所述的青春期抑郁的患者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠。
  9. β-二氢烟酰胺核糖在预防或治疗青春期抑郁的方法，其特征在于，所述方法包括向有需要的受试者给予β-二氢烟酰胺核糖；
    优选地，所述的青春期抑郁的患者为年龄12-24岁的人类，尚未开始性发育的P18-P20年龄组内的小鼠或者开始性发育的青春期P30-P45的小鼠；
    更优选地，所述的青春期抑郁由于长期压力事件应激诱导；
    更优选地，所述的青春期抑郁是由于生命早期压力事件应激诱导产生的。
  10. 一种预防或治疗青春期抑郁的药物，其特征在于，所述药物中以β-二氢烟酰胺核糖为有效成分；
    优选地，所述药物为口服药物、注射药物。
PCT/CN2022/136863 2021-12-08 2022-12-06 二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中的应用 Ceased WO2023104019A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111494276.6 2021-12-08
CN202111494276.6A CN116236498A (zh) 2021-12-08 2021-12-08 二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中的应用

Publications (1)

Publication Number Publication Date
WO2023104019A1 true WO2023104019A1 (zh) 2023-06-15

Family

ID=86624761

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/136863 Ceased WO2023104019A1 (zh) 2021-12-08 2022-12-06 二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中的应用

Country Status (2)

Country Link
CN (1) CN116236498A (zh)
WO (1) WO2023104019A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170081669A1 (en) * 2014-03-18 2017-03-23 Carmel-Haifa University Economic Corp. Ltd Methods for improving cognitive function via modulation of quinone reductase 2
CN108025187A (zh) * 2015-04-28 2018-05-11 新南创新私人有限公司 靶向nad+以治疗化学疗法和放射疗法引发的认知损害、神经病变和不活动
CN112203650A (zh) * 2018-06-21 2021-01-08 雀巢产品有限公司 使用烟酰胺腺嘌呤二核苷酸(nad+)前体和至少一种酮或酮前体的组合物和方法
WO2021180732A1 (en) * 2020-03-09 2021-09-16 Société des Produits Nestlé S.A. Compositions and methods containing reduced nicotinamide riboside for prevention and treatment of neurological diseases and conditions
WO2021231860A1 (en) * 2020-05-14 2021-11-18 Primo Pharmatech Llc Solid dosage form for transmucosal drug delivery

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3156691A1 (en) * 2019-11-01 2021-05-06 Jotiram PALKAR Synergistic nutritional neuroprotective compositions for ameliorating neural dysfunction

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170081669A1 (en) * 2014-03-18 2017-03-23 Carmel-Haifa University Economic Corp. Ltd Methods for improving cognitive function via modulation of quinone reductase 2
CN108025187A (zh) * 2015-04-28 2018-05-11 新南创新私人有限公司 靶向nad+以治疗化学疗法和放射疗法引发的认知损害、神经病变和不活动
CN112203650A (zh) * 2018-06-21 2021-01-08 雀巢产品有限公司 使用烟酰胺腺嘌呤二核苷酸(nad+)前体和至少一种酮或酮前体的组合物和方法
WO2021180732A1 (en) * 2020-03-09 2021-09-16 Société des Produits Nestlé S.A. Compositions and methods containing reduced nicotinamide riboside for prevention and treatment of neurological diseases and conditions
WO2021231860A1 (en) * 2020-05-14 2021-11-18 Primo Pharmatech Llc Solid dosage form for transmucosal drug delivery

Also Published As

Publication number Publication date
CN116236498A (zh) 2023-06-09

Similar Documents

Publication Publication Date Title
Arakawa et al. Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdala and no changes in BDNF levels in the hippocampus at baseline
WO2015103900A1 (zh) 一种多核分子化合物、其制备方法及用途
WO2011153929A1 (zh) 淫羊藿苷和含有淫羊藿苷的淫羊藿黄酮的新用途
WO2023104019A1 (zh) 二氢烟酰胺核糖和烟酰胺单核苷酸在治疗青春期自伤和恶劣环境因素诱导抑郁中的应用
WO2012033235A1 (ko) Ｎ-아세틸-ｌ-시스테인 또는 이의 유도체를 포함하는 불안 장애 치료용 약학 조성물
Ciprandi et al. Comano thermal water inhalations in the treatment of allergic rhinitis: preliminary results
CN105534996B (zh) 一种治疗银屑病的药物组合物
CN108014106A (zh) 卡格列净在制备用于辅助治疗特发性肺纤维化的药物中的应用
CN116098918B (zh) 一种胞磷胆碱药物组合物及其用途
TWI257864B (en) Therapeutic or preventive agent for liver diseases containing a diaminotrifluoromethylpyridine derivative
WO2024035859A1 (en) Combination therapies for treating inflammation
Anisha Ayurvedic management of Premenstrual Syndrome-A Case Study
BRPI0621650A2 (pt) composições farmacêuticas que induzem a liberação do alfa-msh endogênico a partir de células-tronco, e usos de uma substáncia ativa que induz a referida liberação e de alfa-msh sintetizado por qualquer meio
CN114306359A (zh) 白头翁或其提取物的镇痛用途
SE534514C2 (sv) Komposition för behandling av allergiska sjukdomar
CN106361737A (zh) 曲尼司特在制备治疗结核病的药物中的应用
CN101313914A (zh) 喜树果提取物喜果苷的用途及制剂
CN104721189B (zh) 朴莫伐明在制备防治缺血性脑血管病药物中的应用
CN114652706B (zh) 石斛酚及其组合物在制备治疗过敏性皮肤病药物中的应用
WO2019096144A1 (zh) 片仔癀及其制剂在治疗脑卒中后遗症的用途
CN107213216A (zh) 辅助治疗哮喘使用的含化片
WO2019128511A1 (zh) 片仔癀及其制剂在制备治疗带状疱疹后遗神经痛的药物中的用途
CN108420810A (zh) 苯丙酮酸在制备缓解或改善焦虑和抑郁行为的产品中的应用
CN101732334A (zh) 一种预防和治疗脑缺血性中风的组合物
CN101181493A (zh) 治疗癫痫病的药物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22903441

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22903441

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205 DATED 10/04/2025)